Potential Use of Embryonic Stem Cells for the Treatment of Mouse Parkinsonian Models: Improved Behavior by Transplantation of In Vitro Differentiated Dopaminergic Neurons from Embryonic Stem Cells

Nishimura, Fusanori; Yoshikawa, Masahide; Kanda, Seiji; Nonaka, Masahiro; Yokota, Hiroshi; Shiroi, Akira; Nakase, Hiroyuki; Hirabayashi, Hidehiro; Ouji, Yukiteru; Birumachi, Jun-ichi; Ishizaka, Shigeaki; Sakaki, Toshisuke

doi:10.1634/stemcells.21-2-171

Cited by 96 publications

(54 citation statements)

References 64 publications

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“…To investigate further the function of Nurr1-and Pitx3-transduced ES-derived cultures in vivo, mouse or human ES cultures were differentiated to the neural precursor stage (see Materials and Methods) and transplanted into adult mice that had been lesioned with a unilateral intrastriatal injection of the DA neuron toxin 6-hydroxydopamine (6-OHDA). In the absence of transplanted cells, lesioned animals display a characteristic contralateral turning behavior (away from the side of the lesion) when exposed to the DA receptor agonist apomorphine as a result of dennervation-induced hypersensitivity on the lesioned side (28). Transplantation of human or mouse cells transduced with Pitx3 and Nurr1 led to a significantly greater reduction in this turning behavior than did control vector-transduced cells at 6 weeks after cell grafting (Fig.…”

Section: Nurr1 and Pitx3 Induce Murine Es Cell Differentiation To Thementioning

confidence: 89%

“…Stage 3 EB-differentiated human or mouse ES cells were transduced with GFP or Nurr1͞Pitx3͞GFP lentiviruses and then injected (1 ϫ 10 5 cells per l) in the striatum. Apomorphineinduced turning behavior was assessed at 2 weeks after the 6-OHDA injection and before grafting, and again 6 weeks after the cell grafting (28). Mice were placed in hemispheric bowls and left for 20 min to habituate to the new environment.…”

Section: Methodsmentioning

confidence: 99%

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Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

Martinat

Bacci²,

Leete³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

199

158

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Midbrain dopamine (DA) neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson's disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson's disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro, suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures.differentiation ͉ Parkinson ͉ transplantation S everal transcription factors have been implicated in the regulation of mammalian midbrain dopamine (DA) neuron development. Expression of the orphan nuclear receptor transcription factor Nurr1 is initiated in postmitotic midbrain DA neuron precursors at embryonic day 10.5 in the mouse, just preceding expression of tyrosine hydroxylase (TH) (1). Nurr1 is expressed broadly at subsequent stages of development. Nurr1-deficient animals fail to express TH in midbrain DA neurons, but other midbrain DA neuron markers such as Pitx3, Lmx1b, and En1 remain unaltered during development (2-4). Thus, Nurr1 is not required for specification of the early midbrain DA neuron cell fate but does regulate a subset of phenotypic markers. At later stages, Nurr1-deficient mice lack expression of markers for midbrain DA neuron maturation, such as the DA transporter (DAT), which is relatively specific to this cell population.Expression analyses and loss-of-function knockout mouse studies have revealed roles for additional transcription factors in the specification and maturation of midbrain DA neurons, including the homeodomain proteins Lmx1b (5), Pitx3 (6-9), and En1 (10, 11). None of these factors are uniquely expressed in midbrain DA neurons, nor are they required for TH expression. However, each of these factors is necessary for the complete maturation and survival of the midbrain DA neuron population.Overexpression of Nurr1 alone in neuronal cell lines (12), primary neuronal precursor cells (13), or embryonic stem (ES) cultures (14, 15) appears to promote the expression of a subset of midbrain DA neurons markers in vitro, including TH, but this may reflect a broad proneural activity (16). Pitx3 overexpression alone in undifferentiated ES cultures or in neuron progenitor cells is not sufficient to induce a mature midbrain DA neuron phenotype but may promote expression of a subset of markers (13, 17). Thus, we hypothesized that multiple transcription factors may collaborate within a network to induce late events in midbrain DA ...

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Section: Nurr1 and Pitx3 Induce Murine Es Cell Differentiation To Thementioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

Martinat

Bacci²,

Leete³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

199

158

View full text Add to dashboard Cite

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“…Mice were challenged with R(-)-apomorphine (0.6 mg/kg, s.c.), and after cylinder habituation (10 min), the number of net rotations were evaluated in plastic tubes (19 cm diameter, 22 cm high, 30 min) using the video tracking system ANY-maze™ (Stoelting, USA). After four weeks of recovery from 6-OHDA surgery, those animals with insufficient number of net rotations (> 2 counterclockwise rotations/min, fig.1B) (Nishimura et al, 2003) were discarded (around 20-30%/experiment). Selected mice were then individually housed in cages (28 × 17 × 13 cm) with free access either to running wheels (exercise group) or to locked versions of the same wheels (sedentary group).…”

Section: Hemiparkinsonism Dyskinesia and Exercisementioning

confidence: 99%

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice

et al. 2013

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Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice, Neuroscience (2013), doi: http://dx.doi.org/10.1016/j.neuroscience. 2013.03.039 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…The embryoid bodies display regional expression of embryonic markers specific to ecto-, meso-, and endodermal lineages (Gepstein 2002). Exposure to a cocktail of variable growth factors and hormones at adequate dosages and appropriate times allows for the differentiation of ES cells toward various lineages, including cardiomyocytes, pancreatic b cells, hematopoietic progenitors, hepatocytes, neurons, and thyroid follicular cells (Kennedy et al 1997, Keller & Snodgrass 1999, Lumelsky et al 2001, Boheler et al 2002, He et al 2003, Nishimura et al 2003, Ku et al 2004, Shirahashi et al 2004, Foshay et al 2005, Ogawa et al 2005, Arufe et al 2006, Jiang et al 2007.…”

Section: A Stem Cell Overview Definition Of a Stem Cellmentioning

confidence: 99%

Thyroid stem cells: lessons from normal development and thyroid cancer

Thomas

Friedman²,

Lin

2008

Endocrine Related Cancer

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Ongoing advances in stem cell research have opened new avenues for therapy for many human disorders. Until recently, however, thyroid stem cells have been relatively understudied. Here, we review what is known about thyroid stem cells and explore their utility as models of normal and malignant biological development. We also discuss the cellular origin of thyroid cancer stem cells and explore the clinical implications of cancer stem cells in the thyroid gland. Since thyroid cancer is the most common form of endocrine cancer and that thyroid hormone is needed for the growth and metabolism of each cell in the body, understanding the molecular and the cellular aspects of thyroid stem cell biology will ultimately provide insights into mechanisms underlying human disease.

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Potential Use of Embryonic Stem Cells for the Treatment of Mouse Parkinsonian Models: Improved Behavior by Transplantation of In Vitro Differentiated Dopaminergic Neurons from Embryonic Stem Cells

Abstract: Background and Aims. The purpose of the present study was to examine the efficacy of transplantation of mouse embryonic-stem-(ES)-cell-derived tyrosine hydroxylase-positive (TH

Cited by 96 publications

References 64 publications

Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice

Thyroid stem cells: lessons from normal development and thyroid cancer

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